Abstract

Inhibitors of histone deacetylases (HDAC) have been shown to be potent anti-proliferative agents mediated in part by induction of histone acetylation, resulting in growth arrest, cell differentiation and apoptosis. ST80, a novel HDAC inhibitor of the hydroxamate class was investigated for anti-tumor activity towards a panel of human tumor cell lines. At Oncotest a cellular profiling screen was developed in which new compounds are being tested in a standard cell line panel consisting of 42 cell lines from all major solid tumor types. The read-out of the assay is propidium iodide-based fluorescence, which is a measure of viable cell number. For the purpose of mechanism of action (MOA) analysis, the IC50 pattern of the new compounds is compared with the corresponding patterns of 118 agents with a known MOA. Additionally, Compare Analysis can indicate off-target effects of compounds for which targets have previously only been confirmed biochemically. Simultaneously, particularly sensitive and resistant cell lines are identified, helpful for the selection of cell lines and tumor xenografts for follow-up studies like the ex vivo tumor colony assay or in vivo studies using human tumor xenografts growing in nude mice.